1-phenoxy-3-hydroxy-propanones-(2) and a process for their manufacture



Patented Apr. 24, 1945 1 PHENOXY-3-HYDROXY-PROPANONES- 2) AND A PROCESS FOR THEIR MANUFAC- TUBE Adolf Griin and Willy Stoll, Basel, Switzerland, assignors to the firm of J. R. Geigy A. G., Basel,

Switzerland N Drawing. Application November 25, 1941, Se-

rial No. 420,424. In Switzerland December 17,

8 Claims.

Dioxy acetone diethers are already known (diethoxy acetone from Bull. (3) 1, 12 and Ann. 269, 30, other diethers from the U. S. patent applica-. tion Ser. No. 369,356). However, the simple ethers, compounds of the general formula which can be derived diagrammatically from dihydroxy acetone by replacing a hydroxylic hydrogen by an ether radical (a hydrocarbon radical) were hitherto not yet accessible. In the same way as these ether-keto-alcohols, their esters have also remained unknown.

For the production of the compounds of these two classes, the etherification or etherification and esterification of the originating substance, as was to be expected, at least for technical purposes, hardly comes into consideration. According to this invention, however, they are obtained from the halogen derivatives of acetonyl ethers (3 halogen-l-hydroxy acetone ethers) by exchange of the halogen atom for an acyloxy group and further exchange of this group for hydroxyl in the sense of the reaction sequence I to III,

CHaCOONa oHi-o-R 00 onioooozni olnon NaCl In any case the total reaction does not proceed to a sufficient extent under the usual conditions for the halogen exchange, only by boiling the methanolic or ethyl alcoholic solution. However the surprising observation was made that the reaction equilibrium, by increasing the temperature to above 100 0., up to about 150 C., was displaced many times from left to right, and even quantitative reaction can thus be obtained. That not only can the reaction take place practically completely, but the products thereof remain as obtained almost entirely unaltered and can be collected in a very satisfactory yield, is very surprising.

The instability of the already known simple 'u keto alcohols has been known for a long time.

They are liable to rearrangement with the formation of enols, inner semi acetals, cyclic bimers; they can also otherwise isomerise ordisproportionate. Such reactions and their subsequentre actions were naturally to be feared more probably to a greater extent with the new ether-Retoalcohols. In addition; it appeared very easily possible, almost unavoidably, that in the case of the reaction of aryloxy-acetonyl-halides with carboxylic acid salts, whether in the presence or absence of alcohols intramolecular condensations with the splitting oiT of hydrogen halide or Water. the formation of benzofuran or benzopyran derivatives would be'favoured in consequence of the required high temperatures. These by-reactions appear in fact to occur, in many cases, but according to the present invention they never become the main reaction; Of course, it is also advantageous to allow the reaction to proceed in as neutral'a medium as possible. The process enables halogen acetonyl ethers to be converted directly into ether esters of dihydroxy acetone. It is even possible, as already mentioned, to arrive at the dihydroxy acetone mono ethers in one operation and to esterify. these again. 'This is particularly advantageous for the production of a'cetol ether esters of inorganic acids, forexample, of phosphoric acid, pyrophosphoric acid and so forth, 'or' organic acids, the salts of which are less suitable for the direct interreaction with the halogen acetonyl ethers. I

The process has proved as applicable within a wide range. As ether radicals normal and branched alkyls, alkenyls, aryls, aralkyls and other cyclic radicals of various types, which may even be substituted by hetero atoms in any way, may be introduced.

As ester components, acyls of all kinds of oxygenated acids come into consideration, whether of inorganic or organic, mono or'polybasic acids. The starting or intermediate products maybe o tained from mono ethers of glycerine halogen hydrins by oxidation.

It has furthermore been found that it is also possible to arrive at the above described ketoneether-esters in another way, namely by oxidation of the glycerine-ether-ester with a free mid-positioned hydroxyl group of the general formula V R=a suitable ether radical, Y=acyl radical of an: oxygen-containing organic or inorganic acid.

The process formulated by the above'diagram is desirable in many respects, in singular cases an almost indispensable supplement of the other method of production. In that temperatures of about 100 C. and above must be main tained, to exchange the e-position halogen atom for hydroxyacyl, at which temperatures. variousv larly advantageous that according" to the present invention the esters with inorganicacids oi dihydroxyacetone mono others are obtained in one operation from the correspondhig glycerifne ether-esters, whereas it is not possible to prod-nee these (in the same way'as the esters of carboxylic acids) so simply in one operation from the halogen acetonyl-ethers by exchange of: the halogen atom for-the anion of an inorganicacid.

The dihydroxy' acetone mono ethers as well as their esters are suitable for technical purposes, especially for use in the industry-of: pharmaceuticat products, partly as such, partly asintermediate products for other preparations.

The present invention is illustratedby the following examples. The partsareby-weight, unless otherwise stated.

Example 1' 72 parts: of 1--ethoxy-3-chlor.o-propanone:-2 (water clear liquid, soluble waterand organic solvents, point- 1s mm- '76-'29 61.); are added to a.- solution. oi 66. parts of water-free potassium formate in: about-A parts of methanol and neat-.- ed; for hours to; 110-120" C. After ex.- pelling ther methanolabout 'parts=: about 87% of; the quantity. calculated for ethoxy-acetol 61-- ethoxy-3-hydroxy propanone-2.) remain- I-he compound having a boiling. point. 141mm... 109-411. G. is colorless and odorless, solubleinv water; the solution. reduces. slowly when. cold, faster when heated; ammoniacal silver nitrate, but not Fehlings solution.

Instead. of formate there can. be used. acetates, propionates, benzoates of. sodium,, potassium, ammoniumg, alkaline earths. and thelike.

l-ethoxy3-chloro-propanone-2 is produced. as

follows:

100 parts of glycerine monoehlorohydrinethyl ether (I -ethoxy -'3'--chloro-propanol-2, boiling point no mm. 186 G1.) are stirred. with a solution of" '72 parts of crystallised sodium bichromate. and 85- partsof. water at,0-5.- C. For 6 hours. themixtureof parts. of sulfuric acid and. 5.0 parts of water is allowed to flow in. Stirring is continued whilst cooling until. the chromic acidz has, been consumed, extraction. is. efiected, with ether.- and the extracted solution is neutralised vby means, of

the corresponding glycer- 3 (acetate),

bicarbonate, then sodium carbonate. After expelling the solvent 89 parts of l-ethoxy-3-chloropropanone-2 remain.

In the same way as ethoxy-chloro-propanol it is possible to oxidise methoxy-chloro-propanol or the. homologous alkoxy compounds of all kinds for instance propyl, butyl, amyloxy compounds, and the ketones can be further reacted as above described. The alkyls of the alkoxy groups may also be substituted by inert atom groups, for example again by alkoxyl, such as methoxy, ethoxy and so on, by carboxalkyl and many others.

Example 2 Methyl alcoholic: formate solution is reacted under the conditions maintained in the first example with l-propenoxy-3-chloro-propanone z' and produces the all yloxy-acetol (1-propenoxy-3- hydroxy-propanone-Z), boiling point 17 mm.= 118-120 C., a weakly yellowish liquid, without allyl-li-ke odor, which decolorises bromine. and iodine solutions, reduces ammoniacaL silver solution substantially more. energetically than; the ethyl derivative, onheating slowly reduces. even the Fehlings solution.

The corresponding bromopropenoxy compound possesses analogous properties.

I 1-propenoxy-3-chloro-propanone-2 isproduced in the following manner: A mixture of 150 parts of'glycerine chloro-hydrin-allyl ether (l-propenoxy-S-chloro-propanol-Z, boiling, point 22 mm. 101- l03 C1), 101 parts of, sodium bichromate and 80 parts of water is treated gradually at 0 C. with the mixture of" 110 parts. of sulfuric acid. and, 70 parts of water. After complete. reduction. oi the chromic acid 128 parts of the crude product, i. e. over 86% of the. theoretical amount, are isolated by exhaustive extraction, purified by deacidifying and distilling at boiling point 17 mm. -90 C.

Example 3 I00 parts: of 1-phenoxy-3-bromo-propano1-2,,

boiling point 13mm. 162-163 C., by oxidation under the above conditions, react with. methyl alcoholic iormate or acetate solution with quantitative separation of potassium bromide and the formation of phenoxy acetol- (1-phenoxy-3-hydroxy-propanone-2), white crystals, melting point 71 0., well soluble in water and organic solvents; the solution reduces ammon-iacal silver nitrate, but Fehlings solution only very slightly.

The use of bromine derivatives as intermediate products: does not otter any'advantage relatively to that of chlorine compounds. When l-phenoxy-3-chloropropanol 2, boiling point-1s mm. 149 0., is oxidised, the. chlorinated ketone, boiling point. 11; mm. 149450 C. is obtained inbetter' yield than in the case,- of the: bromine analogue: and. with methanol and? potassium iormate or the like this can even produce, almost. quantitatively, reaction to phenoxy-acetol, whilst in any case the temperature is maintained somewhat higher, for example atl30 C.

In the same way as. l-phenoxy-3bromo.-pro-- panol it is possible to oxidise l-orthocresoxybromo-propanol, boiling point. 13mm. 166-167 C., to the-ketone and work this up: further;

Example 4 L-c-methoxyphenoxy 3 chlom-propanone-Z produces, according to the: above directions. in alcoholic solution, when reacted; with formatel-o-methoxyphenoxy-3-hydroxy-propanone-Z, as an aggregate of fine glass-clear needles, melting point 82 C,

l -o-methoxyphenoxy-3-chloro-propanone-2 is produced from glycerine monochlorohydringuaiacol ether (1-o-methoxy-phenoxy-3-chloropropanol-2, a viscous colorless liquid, boiling point 1mm. 150-151 C. by semi-reaction of glycerine-a -dichlorohydrin with guaiacolate or by a round about method, but purer, by reacting epichlorohydrin with potassium guaiacolate and splitting up the epiguaiacoline so obtained by means of hydrochloric acid) by oxidation in a very good yield in the form of a less viscous, orange colored oil, boiling point 1.3 mm. 142-144 C.

The analogous ethoxy compound can be produced from the o-ethoxy phenol by the same reaction sequence as the guaiacol derivative.

Example By reacting l-amyl phenoxy-3-chloropropanone-2 under pressure with alcohol and formate and working up according to the directions in Example 1, the amyl-phenoxy-acetol is obtained, a very highly viscous, yellow liquid boiling point 1.1 mm. 180-181 0., clearly but only slightly soluble in cold water, easily soluble in diluted alcohols and other solvents.

' The starting material is accessible as follows:

Amylphenol when reacted in alkaline solution with epichlorohydrin produces epi-amylphenyline, boiling point 16 mm. 176/1'7'7 0., this on treatment and heating with hydrochloric acid (or even exactly similarl with hydrobromic acid) produces the glycerine chlorohydrin ether of amyl phenol, boiling point 2.5mm. 164-165 C. By oxidation l-amylphenoxy 3 chloro-propanone-2, boiling point 1.5 mm. 172-173" is obtained in excellent yield.

The other C-alkyl derivatives of epiphenyline, which can be produced from the corresponding C-alkyl phenols, for instance the methyl-, propyl, butyland. so on compounds, as well as the analogous arylated epiphenylines, obtainable from epichlorohydrin and the alkali compounds of hydroxydiphenyl, hydroxy phenyl-naphthyl and so forth, further C-aralkylated epiphenlines, for example from hydroxydiphenyl methane, hydroxy-phenylnaphthyl methane, hydroxydiphenylethane, hydroxy stilbene and many others react in the same Way as epi-amylphenyline.

Example 6 According to the particulars of Example 1, 1-m-diethylamino-phenoxy-3-chloropropanone-2 is reacted with formate and methyl alcohol in an autoclave. The crude product is first neutralised with mineral acid, the solution is purified b extraction, then by length shaking with charcoal and finally the free base is separated; 1-(3-diethylaminophenoxy-1')-3-hydroxy propanone-2, a bright yellow oil, boiling point 1.5 mm. 187-189 C., easily soluble in acids and organic solvents. difficultly soluble in hot water, the solution when heated with ammoniacal silver nitrate produces a beautiful mirror.

The starting compound is produced as follows: N-diethyl-m-aminophenol is reacted with potassium hydroxide and epichlorohydrin in the same way as the non-aminated phenols and produces the epihydrin ether of diethyl-aminophenol absolutely pure, boiling point 1 mm. 160-161 C. (1 g consumes for neutralisation 45.5 cc. n/10' acid, calculated 45.3 00.). The compound or its hydrochloride is split up, by taking up a second 7:;

molecule of hydrochloric acid, to the diethylamino-phenyl ether of glycerin chlorohydrin (1- m-diethyl-amino phenoxy-3-chloropropanol-2) a yellow-red oil, as mono acid base, sharply titratable (1 g. uses 39.8 cc. n/ 10 acid, calculated 39.9 cc.). The oxidation to the ketone is effected according to the process which has proved satisfactory with all the compounds of the series.

Into 1-guaiacoxy-3-chloro-propanone-2, heated to C., the same quantity by weight of finely powdered, water-free potassium acetate is stirred gradually. Further stirring takes placewhilst gradually increasing the temperature, periodically to l30 C. until the reaction has finished (i. e. until a sample of the reaction mixture when titrated indicates the calculated quantity of chlorine ion). The product is then extracted from the mixture of potassium chloride and excess ace tate, the solution filtered, evaporated and the residue distilled. By quantitative reaction 1-(2'- methoxyphenoxy)-3-acetoXy-propanone-2 is obtained in excellent yield as a bright yellow liquid, boiling point 1.5 mm. -171 C. identical with the product obtained from the free acetol by acylating. The analogous ethoxy compound can be produced in exactly the same way. Propionate, butyrate,, bromobutyrate, isovalerate, bromoisovalerate or salts of other aliphatic or aromatic carboxylic acids, such as for example of benzoic acid, alkyl benzoic acids, react like acetate or formate in the Examples 1-6 with the formation of the corresponding esters. Only the cheapest carboxylic acids possess a practical importance.

100 parts of (o-methoxy phenoxy)-acetoxypropanone are dissolved in 1000-1500 parts of absolute methyl alcohol and the solution is kept at boiling by reflux for 12-15 hours. The resulting methyl acetate and the methanol excess are then distilled ofi. 76 parts remain (calculated about 78 parts) which after crystallisation exhibit the melting point (from ether) of pure o-methoxy phenoxy-acetol, melting point 82 C. The higher alcohols, ethyl, propyl, butyl alcohol and so on react like methanol in this alcoholysis reaction, but their use does not offer any advantage. Also in this case the cheapest alcohol, which is at disposal, is used advantageously.

Example 8 100 parts of 1-phenoxy-3-acetoxy-propanol-2 are dissolved in 300 parts of glacial acetic acid,

cooling is effected to about 3 C. and whilst stirlowish liquid, boiling point 16mm. 172-474 C. is

identical with l-phenoxy-3-acetoxy-propanone-2.

On boiling its alcoholic solution by reflux formany hours, the free phenoxy-acetol, melting point. 7.1? C., is formed in. addition to ethyl acetate. l

The starting. product, L-phenoxy-3-acetoxypr0 panol-2 is produced. from glycerine-w-halogenhy drinphenyl ether by reacting with acetate; or from monophenyline by means of acetic acid chloride,

or anhydride, or from: epiphenyline by the addition of acetic acid and. heating, then purification by fractionation, boiling pointismm. 190 C.

The oxidation of butryl andisovaleryl-phenylline, produced by splitting up epipheny-line. with butyric: acid or isovaleric acid,-is effected in exactly the same way.

Whatwe claim is:

1. A processfor the manufacture of a. L-phenoxy-3-hydroxypropanone-2, which. comprises reacting, an ether of a 1-hydroxy-3rhalogen-2-propanone of the formula 311mm 30 OHr-halbgen wherein R represents a radical of. the group consisting of phenyl, alkylphenyl, alkoxyphenvl" and alkylaminophenyl, with a, salt ofa carboxylic acid.

and: with a monohydric alcohol;

2'. A process for the manufacture of a l-phenoxy-3-hydroxypropanone-2, which comprises reacting an ether of a l-hydroxy-3-halogenr2-propanone 0f the formula CH1.0.R

| CHz-haloggn wherein R represents a, radical of. the group 0011- wherein R represents av radical of the group; COD:- sisting of phenyl, alkylphenyLalkoxyphenyli and alkylaminophenyl, with. a salt of a carboxyiic acid and; then with a monohydric alcohol.

LA process: for themanufacture of 1-phenoxy-3-hydroxy-propanone-2, which comprises reacting 1-phenoxy-3-halogen-propanone-2 with an alkalt meta-1 formate in presence of methyl alcohol.

'5; A process for the manufacture. of l-phenoxy-3 -hydroxy-propanone-2, which comprises reacting: 1-phenoxy-3 -ha1ogen-propanone-2 with an alkali metal acetate in presence of methyl alcohol.

6. A processfor-the manufacture of 1-,(3'-diethylaminophenoxy-l' 3- hydroxypropanone-2, which comprises reacting l-m-diethylaminophenoxy-3-ch1oropropanone-2 with an alkali metal formate in presence of methyl alcohol.

7.. The compound of the formula.

being a bright yellowoil, boiling point 1,5 mm. 187-189 0., easily soluble in acids and organic solvents difiicultly soluble in hot water; the solution when heated withammoniacal silver'nitrate producing a beautiful: mirror.

8. The compound of the formula CH1.O.C5H

(:0 onion being white crystals, melting point 71 C., well soluble in organic solvents and water, the, aqueous solutions reducing ammoniacal silverv nitrate.

ADOLF Gratin. wniLY STOLL. 

